This proposal will evaluate the effectiveness of a new drug combination, rosiglitazone and clomiphene, for the induction of ovulation in anovulatory women with polycystic ovary syndrome (PCOS). PCOS is a disorder affecting about 5% of women of reproductive age, characterized by anovulation with loss of menstrual cyclicity and hyperandrogenism, often resulting in hirsutism or acne. Anovulation leads to spontaneous infertility and poses a risk of endometrial carcinoma if untreated. A majority of women with PCOS have peripheral insulin resistance and compensatory hyperinsulinemia. These abnormalities may lead to a long-term increased rish of Type 2 diabetes mellitus, hypertension, and accelerated atherosclerosis. Induction of ovulation is necessary to restore fertility to women with PCOS. The standard initial treatment is oral clomiphene citrate, a selective estrogen-receptor modulator which increases endogenous FSH secretion. Clomiphene is successful in inducing ovulation in only about 70% of women with PCOS, and failure is associated with hyperinsulinemia. Women who fail clomiphene ovulation induction are usually treated with parenteral FSH, but this is associated with a greater risk than clomiphene of both multiple gestation and ovarian hyperstimulation syndrome, which in its severe form can be life- threatening. This study will examine whether clomiphene can be more effective in inducing ovulation in women with PCOS when given concomitantly with rosiglitazone, an insulin sensitizer which lowers circulating insulin levels. Women with PCOS selected for previous resistance to clomiphene ovulation induction will be randomized to receive either rosiglitazone or placebo in double-bind fashion for 6 weeks, and then will undergo attempted ovulation induction with clomiphene. If unsuccessful, the clomiphene dose will be increased in up to 2 subsequent cycles in standard fashion in an effort to achieve ovulation. Spontaneous and clomiphene-induced ovulatory outcomes, assessed by serum progesterone levels, will be compared between rosiglitazone and placebo groups and correlated with changes in hyperinsulinemia, assessed on oral glucose tolerance testing (OGTT), and with changes in baseline LH, total and free testosterone, sex hormone binding globulin (SHBG), and insulin-like growth factor binding protein-1 (IGFBP-1) levels. The effects of rosiglitazone on insulin secretion on OGTT will be correlated with its effects on the levels of the above hormones and binding proteins.